The K_2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

Abstract

In multiple sclerosis, demyelination occurs as a consequence of chronic autoimmunity in the central nervous system causing progressive neurological impairment in patients. After a demyelinating event, new myelin sheaths are formed by adult oligodendroglial progenitor cells; a process called remyelination. However, remyelination often fails in multiple sclerosis due to insufficient recruitment and differentiation of oligodendroglial precursor cells. A pivotal role for the twopore-domain potassium (K 2P ) channel, TASK1, has already been proven for an animal model of multiple sclerosis. However, the mechanisms underlying the TASK1-mediated effects are still elusive. Here, we tested the role of TASK1 channels in oligodendroglial differentiation and remyelination after cuprizone-induced demyelination in male mice. We found TASK1 channels to be functionally expressed on primary murine and human, pluripotent stem cell-derived oligodendrocytes. Lack of TASK1 channels resulted in an increase of mature oligodendrocytes in vitro as well as a higher number of mature oligodendrocytes and accelerated developmental myelination in vivo. Mechanistically, Task1-deficient cells revealed a higher amount of phosphorylated WNK1, a kinase known to be involved in the downstream signaling of the myelination regulator LINGO-1. Furthermore, we analyzed the effect of genetic TASK1 ablation or pharmacological TASK1 inhibition on disease-related remyelination. Neither channel inhibition nor lack of TASK1 channels promoted remyelination after pathological demyelination. In summary, we conclude that functional TASK1 channels participate in the modulation of differentiating oligodendroglial cells in a previously unknown manner. However, while being involved in developmental myelination our data suggest that TASK1 channels have no major effect on remyelination. K E Y W O R D S multiple sclerosis, myelination, oligodendrocyte, remyelination, TASK1 channel

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders

“…In multiple sclerosis, insufficient recruitment and differentiation of oligodendroglial precursor cells leads to incomplete remyelination. The demyelination and inflammation in the central nervous system of the mice model of multiple sclerosis was alleviated by treatment with bupivacaine, which acts against TASK-1 as well as other channels [97], but not by specific TASK-1 knockout or inhibition [119,120]. In another mouse model of multiple sclerosis, TASK-1 knockout increased the number of mature oligodendrocytes and accelerated developmental myelination, yet it did not affect oligodendroglial differentiation during remyelination after pathological demyelination [97].…”

“…Glia support neuronal functions via various mechanisms in the central nervous system, and K2P channels are expressed in glia. A transcriptome analysis detected the mRNAs encoding TWIK-1 and TREK-1 in astrocytes [96], and immunohistochemistry detected TASK-1 protein in astrocytes of hippocampus and oligodendrocytes in the mouse brain [97]. Several studies have examined the functions of K2P channels in glia (Figure 2), though much more work remains to be done.…”

“…The primary function of oligodendrocytes is to insulate the neuronal axon by creating a myelin sheath, which contributes to rapid signal transduction. TASK-1 can induce currents in oligodendrocytes in response to extracellular acidification, and lack of TASK-1 depolarizes oligodendroglial precursor cells [97]. Inhibition of TASK-1 can protect oligodendrocytes from ischemic injury [118].…”

“…The demyelination and inflammation in the central nervous system of the mice model of multiple sclerosis was alleviated by treatment with bupivacaine, which acts against TASK-1 as well as other channels [97], but not by specific TASK-1 knockout or inhibition [119,120]. In another mouse model of multiple sclerosis, TASK-1 knockout increased the number of mature oligodendrocytes and accelerated developmental myelination, yet it did not affect oligodendroglial differentiation during remyelination after pathological demyelination [97]. Future studies should clarify whether and how TASK-containing K2P channels help mediate oligodendroglial differentiation and remyelination in normal and disease contexts.…”

Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS

“…9, 82152 Planegg-Martinsried, Germany. 2 Institute of Neuropathology, University Hospital Münster, Münster, Germany. 3 Therapeutic Immune Design, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.…”